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Comparative effectiveness of primary radiotherapy versus surgery in elderly patients with locally advanced oropharyngeal squamous cell carcinoma
Oral Oncology 88 (2019) 18–26
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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Comparative effectiveness of primary radiotherapy versus surgery in elderly patients with locally advanced oropharyngeal squamous cell carcinoma
T
⁎
David J. Shera, , Jingsheng Yanb, Andrew Dayc, Baran D. Sumerc, Nhat-Long Phamd, Saad Khane, Hong Zhub a
Department of Radiation Oncology and Division of Outcomes and Health Services Research, UT Southwestern Medical Center, Dallas, TX, USA Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, USA c Department of Otolaryngology-Head & Neck Surgery, UT Southwestern Medical Center, Dallas, TX, USA d Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA e Department of Medical Oncology, UT Southwestern Medical Center, Dallas, TX, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Oropharynx cancer Chemoradiotherapy Combined-modality therapy SEER-Medicare
Objectives: To determine the comparative effectiveness of primary radiotherapy (RT) and primary surgery (PS) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: Eligible individuals were patients in the SEER-Medicare registry diagnosed with locally advanced OPSCC between 2000 and 2011. Patients were categorized as receiving either primary RT ± chemotherapy, or PS ± adjuvant RT or chemoradiotherapy (CRT). Overall survival (OS) was analyzed using Cox multivariable analysis (MVA). Risks of gastrostomy dependence (GD), esophageal stricture (ES), and osteoradionecrosis (ORN) were analyzed using logistic regression. Results: A total of 2754 patients (69% RT, 31% PS) were included in this cohort, with a median age of 72 years. Patients treated with RT, CRT and PS experienced 3-year OS outcomes of 36.1%, 52.8%, and 54.9%, respectively (p < 0.001). Increasing age, unmarried status, increasing comorbidity, lower income, base of tongue (BOT) site, higher stage, no prior PET, and RT alone (but not CRT) were associated with inferior OS. Independent predictors of GD at 6 months included black race, BOT site, advanced stage, and CRT. The risks of ORN and stricture were not associated with treatment modality. Concurrent chemotherapy improved OS with definitive RT but had no impact in adjuvant RT. Only cisplatin- and taxane-containing regimens improved OS, but all concurrent agents, including cetuximab, significantly worsened GD. Conclusion: Local therapy decisions for locally advanced OPSCC must be individualized, with CRT increasing acute and chronic GD. The differential survival impact of concurrent chemotherapy in the definitive and adjuvant setting may be a consideration in decision-making.
Introduction The prevalence of oropharyngeal squamous cell carcinoma (OPSCC) has increased dramatically, and it is now the most commonly diagnosed head and neck malignancy in the United States [1]. This increase, driven by human papillomavirus (HPV) infection, has been seen in elderly populations as well [2]. As radiotherapy and surgical techniques have improved, primary surgical therapy and radiation therapy are both viable treatment approaches for this disease. The opportunity to spare patients the toxicity of concurrent chemoradiotherapy (CRT) or even any adjuvant radiotherapy (RT) is the main benefit of surgery, whereas eliminating any immediate surgical risk or delayed surgical complication are strengths of definitive RT or CRT. ⁎
Outcome comparisons between upfront surgery and radiotherapy are generally small and all retrospective, as two prospective trials will not be completed for several years [3]. The general consensus from these studies is that survival outcomes are not significantly different [4,5], but the potential to minimize the exposure of patients to CRT and its complications may favor an initial surgical approach [6,7]. Yet there is a gap in comparing these two locoregional modalities in the elderly, which comprises a significant percentage of the afflicted population [8]. Given the well-known toxicities in delivering concurrent chemotherapy to older patients, the therapeutic ratios of these two treatments take on added importance. In this study, we have used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to compare survival and toxicity
Corresponding author at: Department of Radiation Oncology, UT Southwestern Medical Center, 5810 Forest Park Drive, Dallas, TX 75390, USA. E-mail address: [email protected] (D.J. Sher).
https://doi.org/10.1016/j.oraloncology.2018.11.004 Received 28 August 2018; Received in revised form 26 October 2018; Accepted 3 November 2018 1368-8375/ © 2018 Published by Elsevier Ltd.
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outcomes in elderly patients with locally advanced OPC treated with upfront surgery versus definitive RT or CRT. We compared overall survival outcomes, as well as gastrostomy use and dependence, esophageal stricture, and osteonecrosis, in order to understand the therapeutic ratios of these two competing treatments. Moreover, we analyzed the differential importance of concurrent chemotherapy in the definitive and postoperative settings, including a focus on the impact of alternative chemotherapy regimens. Methods Data sources This cohort was created from the Surveillance, Epidemiology and End Results (SEER)-Medicare database, which links health care claims for fee-for-service Medicare enrollees with patient demographic and tumor-specific data recorded by SEER cancer registries. The Medicare program provides health care benefits to 97% of the U.S. population aged 65 years or older, and approximately 94% of SEER patients 65 years or older have been successfully linked with their Medicare claims [9]. Cohort definition Fig. 1 details the inclusion and exclusion characteristics that defined the cohort composition. Patients were aged 66 years or older and diagnosed with “regional” or “distant” squamous cell carcinoma of the oropharynx (Table 1) between the years 2000 and 2011, and Part A/B coverage was mandatory for 1 year prior diagnosis to 1 year following diagnosis. Because some locally advanced primary tumors were coded as “distant” historical stage in the SEER registry (e.g. extension to larynx/hypopharynx, mandible, extrinsic tongue musculature, other bone or hard palate), patients with this stage were included in the analysis. The first treatment (either surgery, RT, or chemotherapy) was required to have started within 6 months of diagnosis. Patients needed to receive either definitive surgery or definitive RT for inclusion. Treatment assignments Claims for at least 20 RT fractions were required for patients to have been coded as receiving curative-intent radiotherapy, within 12 weeks of starting treatment; shorter regimens may have been palliative in intent. Concurrent chemoradiotherapy was defined by a chemotherapy claim between 3 weeks prior to starting RT and the end of RT. Chemotherapy delivered prior to 3 weeks before RT was considered induction therapy, and these patients were excluded, since subsequent radiotherapy selects for favorable responders. Adjuvant RT was assigned after surgery if the first RT claim was present within 90 days of surgery, and adjuvant CRT was assigned if chemotherapy was administered between 3 weeks before RT to the last RT claim. Patients who underwent a diagnostic tonsillectomy without neck dissection were classified as receiving primary RT. Diagnostic lymph node excisions were not considered as a primary surgery; only neck dissections were considered a curative-intent operation. Chemotherapy agents were categorized as cisplatin, carboplatinonly, taxane-containing (including doublets with a platinum), cetuximab-only, and other.
Fig. 1. Cohort definition.
that time may have had dysphagia from disease progression. The date of last use was the last claim for nutrition. The presence of a clinically relevant early esophageal stricture was defined as a dilation code within the first year of surviving patients. The presence of a clinically relevant bone complication was coded using the methodology of Beadle et al. [10] One year was chosen as the primary analysis for these latter two toxicities since subsequent procedures may be more likely due to disease progression. For gastrostomy dependence analyses at 6 and 12 months, the denominators were patients alive at 6 and 12 months, respectively.
Outcomes
Chemotherapy analyses
Overall survival was calculated from the date of diagnosis to the date of death. All patients were analyzed for toxicity endpoints, with stage serving as a covariate. Gastrostomy use was evaluated at 3 time points: any, 6 months or longer, and 12 months or longer. Gastrostomy use required a claim for enteral nutrition from diagnosis to 3 months from the last treatment; patients who first used enteral feedings after
We performed several sensitivity analyses on the relative benefits and harms of chemotherapy in these two cohorts. First, an interaction term was placed in the multivariable model for overall survival to assess whether the primary therapy modality (i.e. RT or surgery) was an effect modifier of the impact of chemotherapy. Subset analyses were then performed in primary radiotherapy patients and in surgical patients 19
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Table 1 (continued)
Table 1 Patient characteristics. Abbreviations: SE = standard error; CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. PET = positron emission tomography. Characteristic
Patient characteristics Age (median, IQR) Age (quartile) ≤68 69–72 73–77 ≥78 Gender Female Male Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure Yes No SEER region Northeast South Midwest West Median census tract income ≤25% 25–50% 50–75% ≥75% Area of residence Metropolitan Nonmetropolitan % HS diploma ≤70% 70–85% 85–90% ≥90% Disease characteristics Primary site Tonsil Base of tongue Other Historic stage Regional Distant Grade I II III Other
Entire cohort (n = 2754)
Primary radiotherapy (n = 1913)
Primary surgery (n = 841)
P value
72, 69–77
73, 69–78
71, 68–76
< 0.001 < 0.001
665 750 678 661
434 511 470 498
231 239 208 163
(24%) (27%) (25%) (24%)
(23%) (27%) (25%) (26%)
Characteristic
Chemotherapy Cisplatin Carboplatinonly Taxanecontaining Cetuximabonly Other RT modality 2D/3D IMRT PET use Yes No
(27%) (28%) (25%) (19%) 0.522
776 (28%) 1978 (72%)
546 (29%) 1367 (71%)
230 (27%) 611 (73%)
2429 (88%) 214 (8%) 111 (4%)
1682 (88%) 160 (8%) 71 (4%)
747 (89%) 54 (6%) 40 (5%)
1490 (54%) 1264 (46%)
1019 (53%) 894 (47%)
471 (56%) 370 (44%)
0.107
Entire cohort (n = 2754)
Primary radiotherapy (n = 1913)
Primary surgery (n = 841)
596 (39%) 108 (7%)
515 (39%) 95 (7%)
81 (41%) 13 (12%)
322 (21%)
286 (21%)
36 (11%)
365 (24%)
331 (25%)
34 (17%)
141 (9%)
108 (8%)
33 (17%)
1689 (71%) 675 (29%)
1351 (71%) 562 (29%)
338 (75%) 113 (25%)
1583 (57%) 1171 (43%)
1207 (63%) 706 (37%)
376 (45%) 465 (55%)
P value
< 0.001
0.068
< 0.001
who received adjuvant radiotherapy. 0.184
Statistical methods
0.113 1392 (51%) 655 (24%) 244 (9%) 198 (7%)
965 474 185 146
(50%) (25%) (10%) (8%)
1669 (61%) 1085 (39%)
1162 (61%) 751 (39%)
507 (60%) 334 (40%)
499 (18%) 779 (28%) 279 (10%) 1197 (43%)
321 585 181 826
178 (21%) 194 (23%) 98 (12%) 371 (44%)
Summary statistics for patient characteristics were reported using medians and interquartile ranges (IQR) for continuous variables, and using counts and percentages for categorical variables. Patient characteristics, disease characteristics, and treatment characteristics were compared between primary radiotherapy and primary surgery using the χ 2 -test. The overall survival was estimated using the Kaplan-Meier method. Median survival time and 95% confidence intervals (CI) were reported. Univariable and multivariable Cox regression analyses were used to assess the association between the overall survival and patient, disease, treatment characteristics. Variables with a univariable p-value of 0.2 or less were entered in a backward selection algorithm to yield the parsimonious multivariable regression model. The assumption for proportional hazards was evaluated by using scaled Schoenfeld residuals. Hazard ratios and 95% confidence intervals (CI) were reported. Univariable logistic regression and multivariable logistic regression with the backward selection algorithm were used to identify the predictors for toxicity endpoints at 1 and 3 years. Odds ratios and 95% confidence intervals (CI) were reported. Two-sided p-values were reported and a p-value less than 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4 (Cary, NC).
427 (51%) 181 (22%) 59 (7%) 52 (6%) 0.821
< 0.001 (17%) (31%) (9%) (43%)
0.826 217 (8%) 1404 (51%) 750 (27%) 360 (14%)
156 978 518 246
(8%) (51%) (27%) (13%)
61(7%) 426 (51%) 232 (28%) 114 (14%)
2292 (83%) 462 (17%)
1578 (82%) 335 (18%)
714 (85%) 127 (15%)
562 902 475 792
405 643 305 545
157 259 170 247
0.119
0.023 (20%) (33%) (17%) (29%)
(21%) (34%) (16%) (28%)
(19%) (31%) (20%) (29%)
Results Patient and treatment characteristics
0.391 933 (34%) 1297 (47%) 524 (19%)
633 (33%) 915 (48%) 365 (19%)
300 (36%) 382 (45%) 159 (19%)
2285 (83%) 469 (17%)
1585 (83%) 328 (17%)
700 (83%) 141 (17%)
140 (5%) 955 (35%) 1047 (38%) 612 (22%)
96 (5%) 642 (34%) 681 (36%) 494 (26%)
44 (5%) 313 (37%) 366 (44%) 118 (14%)
578 (30%) 1335 (70%)
0 0
0 0 0
390 (46%) 254 (30%) 197 (23%)
Patient characteristics (n = 2754) are shown in Table 1. The median age of the cohort was 72 years, and the majority (72%) of patients were male. Nearly 88% of the individuals were white. There was a smokingrelated claim in 61% of all patients. The historic stage was regional and distant in 83%, and 17%, respectively. Primary radiotherapy was used in 69% of all patients; out of these individuals, radiation alone and concurrent chemotherapy were implemented in 30% and 70% of the group, respectively. Patients treated with radiotherapy alone were slightly but significantly more likely to have higher Charlson-Deyo comorbidities scores (50% vs 56%, 27% vs. 27%, 14% vs 9%, and 9% vs. 8% with scores of 0, 1, 2, and 3–7, for RT vs. CRT, respectively, p = 0.022). These individuals were also older (median 76, IQR 70–81 years) than those treated with CRT (median 71, IQR 68–76 years, p < 0.001). Patients older than 72 years (median) were less likely to receive any concurrent systemic therapy (44% vs. 53%, p < 0.001), and of those patients receiving systemic treatment, older patients were more likely to receive cetuximab (34% vs. 18%, OR
0.807
< 0.001
Treatment characteristics Primary RT RT alone 578 (30%) Concurrent 1335 (70%) CRT Primary surgery Surgery only 390 (47%) Adjuvant RT 254 (30%) Adjuvant CRT 197 (23%)
20
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Table 2 Overall survival results. A hazard ratio over 1 means increased mortality. Abbreviations: SE = standard error; CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery + C/RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
3-year survival % (SE)
Univariable Analysis (95% CI)
Multivariable analysis
62.9 56.5 48.2 31.3
(2.0) (2.0) (2.1) (1.9)
Reference 1.24 (1.07–1.44) 1.56 (1.35–1.80) 2.49 (2.16–2.87)
Reference 1.24 (1.06–1.46) 1.50 (1.28–1.75) 2.03 (1.74–2.38)
51.1 (1.2) 46.2 (1.9)
Reference 1.21 (1.09–1.34)
51.3 (1.1) 36.0 (3.5) 42.6 (5.2)
Reference 1.43 (1.21–1.69) 1.15 (0.89–1.48)
55.3 (1.4) 43.4 (1.5)
Reference 1.47 (1.33–1.61)
Reference 1.32 (1.18–1.46)
56.8 44.7 35.0 25.6
(1.4) (2.1) (3.4) (3.5)
Reference 1.54 (1.37–1.73) 1.81 (1.53–2.14) 2.34 (1.96–2.79)
Reference 1.51 (1.34–1.71) 1.63 (1.37–1.93) 1.93 (1.61–2.31)
50.0 (1.6) 50.5 (1.3)
Reference 0.99 (0.90–1.10)
51.0 50.6 48.5 45.8
(1.6) (2.4) (1.9) (3.2)
Reference 1.07 (0.93–1.22) 1.08 (0.96–1.21) 1.15 (0.98–1.36)
58.8 51.5 48.5 35.8
(2.8) (2.0) (1.4) (3.4)
Reference 1.24 (1.04–1.47) 1.27 (1.08–1.48) 1.75 (1.42–2.16)
49.6 (1.1) 50.2 (2.5)
Reference 0.97 (0.85–1.11)
53.8 51.8 47.6 45.1
(1.9) (2.5) (1.8) (2.2)
Reference 1.07 (0.92–1.24) 1.12 (0.99–1.27) 1.26 (1.10–1.45)
55.6 (1.8) 50.3 (1.5) 38.0 (2.3)
Reference 1.16 (1.04–1.29) 1.60 (1.40–1.82)
44.4 (4.4) 46.7 (1.7) 51.1 (1.7)
Reference 0.95 (0.77–1.18) 0.81 (0.66–1.01)
53.1 (1.1) 33.4 (2.4)
Reference 1.70 (1.50–1.92)
Reference 1.77 (1.55–2.02)
54.9 (1.8) 36.1 (2.1) 52.8 (1.5)
Reference 1.59 (1.40–1.80) 1.03 (0.92–1.15)
Reference 1.24 (1.08–1.42) 1.06 (0.94–1.20)
48.7 (1.3) 55.9 (2.2)
Reference 0.82 (0.72–0.93)
59.5 (1.4) 37.8 (1.5)
Reference 1.68 (1.52–1.85)
P value
< 0.001
< 0.001
< 0.001
0.018 Reference 1.02 (0.86–1.22) 1.10 (0.94–1.30) 1.37 (1.09–1.72)
< 0.001 Reference 1.19 (1.06–1.34) 1.43 (1.24–1.65)
< 0.001
0.008
< 0.001 Reference 1.62 (1.46–1.81)
site surgery only, and 173 (21%) underwent neck dissection only.
2.41 (95% CI 1.87–3.11, p < 0.001). Of the patients treated with initial surgery, 47%, 30%, and 23% received no adjuvant therapy, adjuvant radiotherapy, and adjuvant chemoradiotherapy, respectively. Of the 841 patients who underwent surgery, 371 (44%) underwent primary site surgery plus neck dissection, 297 (35%) received primary
Overall survival The median follow-up duration for surviving patients was 3.3 years. 21
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Fig. 2. Overall survival.
term gastrostomy dependence were similar to any dependence, including treatment (p < 0.001), except radiation alone was almost significantly improved in comparison to primary surgery (OR 0.76, 95% CI 0.55–1.03). Finally, 20% (n = 406) of surviving patients were gastrostomy-dependent at least one year from the end of treatment. Multivariable regression disclosed several variables predictive of long-term gastrostomy dependence, including older age, non-married status, base of tongue primary site, and advanced stage. Treatment with CRT (OR 1.66, 95% CI 1.28–2.15) but not RT alone (OR 0.84, 95% CI 0.58–1.22) was strongly associated with gastrostomy-dependence at one year in comparison to surgery.
Table 2 shows the univariable and adjusted predictors of overall survival. Younger age, married status, lower comorbidity score, higher census tract income, tonsil site, regional (versus distant) stage, PET use, and treatment type (p < 0.001) were all associated with improved survival. Using primary surgery as the reference, radiation alone was significantly related to inferior survival (HR 1.24, 95% CI 1.08–1.42), whereas there was no difference between CRT and surgery (HR 1.06, 95% CI 0.94–1.20). Survival curves are shown in Fig. 2. Sensitivity analyses on survival In the first sensitivity analysis, we excluded patients from the surgical cohort who underwent a non-transoral surgery (n = 172). The results were essentially identical. We also performed a subset analysis of locally advanced patients treated with RT, CRT or primary site surgery plus neck dissection. In this regression, treatment type was again associated with overall survival (p = 0.035), but the distinction was between surgery and RT (HR 1.20, 95% CI 1.01–1.42) and not surgery and CRT (HR 1.02, 95% CI 0.87–1.20).
Esophageal dilation The crude risk of esophageal dilation within one year of the end of treatment was 4.3% (n = 88) for surviving patients. On multivariable analysis, only region (Northeast, South, and Midwest all significantly greater than West) were associated with increased risk of stricture. Treatment type was not associated with this toxicity. Among 3 year survivors, chemoradiotherapy was actually protective on multivariable analysis, with the OR 0.62 (95% CI 0.43–0.91) in comparison to primary surgery (p = 0.0042 for the 3-way comparison).
Gastrostomy dependence Enteral feeding was evaluated in 3 ways: any enteral feeding, gastrostomy use past 6 months from the end of last treatment, and gastrostomy use past 12 months from the end of last treatment. Table 3 shows the multivariable predictors of any gastrostomy use. Among all patients, 43% (n = 1182) of individuals used enteral feeding at some point in the first year of treatment. Treatment type was associated with any gastrostomy use (p < 0.0001), with chemoradiotherapy significantly increasing the risk of enteral feedings (OR 2.44, 95% CI 2.04–2.93) over primary surgery; patients treated with radiotherapy alone were not significantly more likely to require a gastrostomy (OR 0.96, 95% CI 0.76–1.21). A total of 21% (n = 632) of all patients were gastrostomy-dependent past 6 months (Table 4). The multivariable predictors of medium-
Bone toxicity Ninety-seven surviving patients (4.7%) experienced a bone toxicity within the first year of finishing radiotherapy. No patients treated with surgery alone developed a bone toxicity. In restricting the analysis to patients who received radiation therapy, there were no significant predictors of osteonecrosis on multivariable analysis. There was also no relationship between treatment and osteonecrosis when restricting the analysis to 3 years survivors.
22
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Table 3 Use of gastrostomy tube at any point. Abbreviations CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery and RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
Gastrostomy use %
Univariable analysis (95% CI)
41.5 44.8 44.5 40.5
Reference 1.14 (0.93–1.413) 1.13 (0.91–1.405) 0.96 (0.77–1.196)
43.6 41.2
Reference 0.91 (0.77–1.075)
43.3 43.5 33.3
Reference 1.01 (0.76–1.334) 0.65 (0.44–0.979)
45.4 40.0
Reference 0.80 (0.69–0.936)
45.2 46.3 43.3 36.9
Reference 1.04 (0.87–1.258) 0.93 (0.71–1.226) 0.71 (0.52–0.963)
38.3 45.9
Reference 1.36 (1.17–1.594)
42.0 40.7 44.7 45.9
Reference 0.95 (0.77–1.170) 1.11 (0.93–1.336) 1.17 (0.90–1.520)
41.1 42.1 43.5 46.1
Reference 1.04 (0.81–1.346) 1.10 (0.87–1.396) 1.22 (0.87–1.719)
42.5 45.0
Reference 1.11 (0.91–1.355)
42.4 41.9 44.2 42.9
Reference 0.98 (0.78–1.232 1.08 (0.89–1.305) 1.02 (0.82–1.268)
37.8 48.7 37.6
Reference 1.56 (1.32–1.853) 0.99 (0.79–1.234)
42.9 45.2 41.7
Reference 1.10 (0.77–1.576) 0.96 (0.67–1.364)
42.7 44.1
Reference 1.06 (0.87–1.297)
32.6 30.8 54.7
Reference 0.92 (0.73–1.157) 2.50 (2.09–2.989)
45.5 48.2
Reference 1.11 (0.93–1.329)
48.4 35.5
Reference 0.59 (0.50–0.686)
Multivariable analysis
P value
< 0.001 Reference 1.34 (1.14–1.57)
< 0.001 Reference 1.51 (1.26–1.80) 1.00 (0.80–1.26)
< 0.001 Reference 0.96 (0.76–1.21) 2.44 (2.04–2.93)
was significant (HR 0.70, p = 0.03). This result means that the impact of concurrent chemotherapy is significantly different in the definitive and adjuvant setting: it is beneficial in primary RT patients but detrimental in primary surgery patients (adjusted HR 1.28, 95% CI 0.95–1.71). Indeed, when just analyzing patients who received surgery
Chemotherapy In a subset analysis restricted to patients receiving radiotherapy, with concurrent chemotherapy as an independent variable and an interaction term for primary therapy*chemotherapy, the interaction term 23
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Table 4 Use of gastrostomy tube at 6 months. Abbreviations CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery and RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
Gastrostomy use %
Univariable analysis (95% CI)
Multivariable analysis
26.2 24.7 30.5 27.2
Reference 0.92 (0.71–1.20) 1.24 (0.95–1.61) 1.05 (0.80–1.39)
Reference 0.92 (0.70–1.20) 1.32 (1.01–1.73) 1.21 (0.91–1.62)
26.5 28.6
Reference 1.11 (0.91–1.37)
26.6 34.7 21.4
Reference 1.47 (1.05–2.04) 0.75 (0.44–1.28)
27.4 26.6
Reference 0.96 (0.80–1.16)
26.9 29.8 31.7 26.1
Reference 1.15 (0.92–1.45) 1.26 (0.90–1.76) 0.96 (0.64–1.43)
25.4 28.1
Reference 1.15 (0.94–1.39)
26.3 26.6 27.2 30.5
Reference 1.02 (0.78–1.32) 1.04 (0.83–1.31) 1.23 (0.90–1.69)
24.9 26.7 27.8 28.9
Reference 1.10 (0.80–1.51) 1.16 (0.87–1.56) 1.23 (0.80–1.88)
27.0 27.5
Reference 1.03 (0.80–1.32)
27.5 26.9 26.1 29.0
Reference 0.97 (0.73–1.29) 0.93 (0.73–1.18) 1.08 (0.82–1.41)
22.3 31.7 24.1
Reference 1.62 (1.31–2.01) 1.11 (0.83–1.47)
27.6 28.8 27.4
Reference 1.06 (0.67–1.67) 0.99 (0.63–1.56)
25.7 34.3
Reference 1.51 (1.18–1.93)
Reference 1.39 (1.08–1.80)
21.4 17.8 34.2
Reference 0.80 (0.59–1.08) 1.91 (1.53–2.39)
Reference 0.76 (0.55–1.03) 1.83 (1.46–2.30)
28.4 29.1
Reference 1.04 (0.83–1.29)
28.5 24.9
Reference 0.83 (0.69–1.01)
P value
0.027
0.046 Reference 1.48 (1.049–2.08) 0.77 (0.446–1.32)
< 0.001 Reference 1.52 (1.22–1.89) 1.11 (0.83–1.48)
0.010
< 0.001
When categorizing chemotherapy into specific agents among patients treated with primary radiotherapy, a significant survival benefit (Table 5) over radiotherapy alone was restricted to treatment with cisplatin (HR 0.78, 95% CI 0.65–0.93) or a taxane-containing regimen (HR 0.77, 95% CI 0.64–0.94) (Table 5). In fact, there was a trend for
and adjuvant RT or adjuvant CRT, there was no association between chemotherapy and survival (multivariable HR 1.1, 95% CI 0.84–1.52, p = 0.42). In contrast, among patients treated with primary radiotherapy, the use of chemotherapy was clearly associated with improved survival (HR 0.86, 95% CI 0.75–0.98, p = 0.03). 24
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Table 5 Impact of chemotherapy agent and outcome for patients receiving chemoradiotherapy. A hazard ratio over 1 means increased mortality. Abbreviations: AHR = adjusted hazard ratio; AOR = adjusted odds ratio. Chemotherapy
None Cisplatin Carboplatin-only Taxane-containing Cetuximab-only Other
3-Year Overall Survival
Any Gastrostomy
6-Month Gastrostomy
Stricture
%
AHR
%
AOR
%
AOR
%
AOR
36.1 59.8 44.7 59.2 39.9 48.3
Reference 0.78 (0.65–0.93) 0.79 (0.59–1.06) 0.77 (0.64–0.94) 1.16 (0.95–1.40) 0.82 (0.64–1.06)
30.8 56.5 52.6 57.3 51.7 50.0
Reference 2.74 (2.13–3.52) 2.35 (1.51–3.66) 2.86 (2.12–3.84) 2.27 (1.72–3.01) 2.16 (1.42–3.29)
17.8 34.3 32.1 37.9 30.3 37.0
Reference 2.58 (1.86–3.60) 2.07 (1.20–3.59) 2.89 (2.01–4.16) 1.95 (1.35–2.82) 2.96 (1.80–4.87)
11.9 7.4 13.7 6.6 7.6 11.1
Reference 0.61 (0.40–0.92) 1.26 (0.66–2.39) 0.50 (0.29–0.85) 0.63 (0.39–1.02) 0.89 (0.46–1.71)
In contrast, postoperative CRT did not add improve survival in comparison to adjuvant radiotherapy alone, suggesting surgery may be preferable in operable patients who may poorly tolerate concurrent chemotherapy. This result is hypothesis-generating, especially since information on margin status and other high-risk features was not available. On one hand, this difference may simply reflect the fact that the randomized data show a more questionable benefit to concurrent chemotherapy in the adjuvant setting [15]; on the other hand, one may argue that the risks of postoperative CRT are particularly pronounced in the elderly population, counterbalancing a smaller potential oncologic gain from the more intensive therapy. This analysis has also shown that while all concurrent drugs significant increased the risk of gastrostomy-dependence, only cisplatin and taxane-containing regimens led to a survival benefit. Carboplatin was not associated with improved survival, and most notably, cetuximab appeared to impair survival. This latter result confirms a similar finding on the adverse effect of the drug in elderly patients on the original Bonner trial [16], strongly arguing against its use in this population. Finally, it is also worth mentioning the potent improvement in overall survival (absolute difference over 20%) among patients staged with PET, a result that was maintained on multivariable regression. There are several possible explanations for this result, including the increased detection of occult metastatic disease, thus reducing the risk of local therapy in a patient with disseminated disease; stage migration from PET use has been seen in other disease sites [17]. The imaging information may have also facilitated superior local therapy through better radiotherapy targeting or even surgical planning. Finally, the use of PET may be a general marker of higher quality care, which could have improved survival through mechanisms not otherwise characterized. Claims-based studies suffer from several well-known limitations, and this analysis is no exception. While the analysis did control for smoking claims, the database does not include information on HPV or p16 status, and therefore an imbalance between treatment modalities may have confounded the results. The study only applies to elderly patients, and whether the same result would be seen in a younger cohort is unknown. This report is a retrospective analysis, and there is significant selection bias in which patients received initial surgical versus radiotherapeutic treatment. Because operative patients tend to be healthier with lower-volume disease, both survival and functional outcomes would be expected to be better. Similarly, the survival decrement seen in patients who received radiotherapy alone may partially relate to comorbid conditions that prevented the patient from receiving concurrent chemotherapy. In addition, the SEER-Medicare database does not provide information on recurrence patterns, so one cannot know whether locoregional control is superior with one treatment approach. Also, while we determined claims-based toxicities, ultimately patient-reported outcomes are the most important functional metric. Enteral feeding is only one measure of dysphagia, and does not include other aspects of swallowing that may be different in the two primary treatment
increasing mortality with use of cetuximab (HR 1.16, 95% CI 0.95–1.40). On the other hand, all concurrent regimens increased the risk of gastrostomy by over a factor of 2, which was significant at 6 months as well.
Discussion In this study, we have shown that in elderly individuals with locally advanced OPSCC, initial surgery is superior to RT alone but not CRT. Given that CRT is considered the standard-of-care in higher-stage disease [11], these findings confirm the absence of a significant survival difference between the standardly recommended surgical- and radiotherapy-based treatments for this condition [11,12]. Two literature reviews have suggested similar results [6,7], and the present study adds convincing, additional population-based data supporting this conclusion, despite a significant bias favoring primary operative therapy, including both selection bias for surgical candidacy and stage migration for more accurately staging surgical patients. In contrast, the late toxicity profiles differed by primary treatment modality. In particular, patients treated with definitive CRT experienced a significantly greater (and clinically meaningful) risk of any, 6month, and 12-month gastrostomy dependence in comparison to those treated with RT alone or initial surgery. Planning with IMRT has improved dramatically since the time of this study, and modern dysphagia-avoidance based planning may minimize the need for enteral support in patients treated today; of course, such improvements would be expected in the RT alone and postoperative settings as well. Nevertheless, dysphagia and chewing, in addition to xerostomia, dominate the chronic toxicity profile in patients treated for OPC [13]. Thus, while it is critical to recognize that operative patients are often selected for their lower volume, resectable disease as well as their potential for superior functional status and recovery, these data support the contention that avoiding concurrent CRT in this population will substantially improve their dysphagia. On the other hand, treatment modality was not associated with the need for an additional procedure to treat osteonecrosis, either at 1 or 3 years. This result does strongly suggest that differences in radiation dose with definitive versus adjuvant therapy either do not influence these complications, or the reduced dose is counteracted by the additional risk of surgical intervention. In addition, there was actually an increased risk of esophageal dilation among patients treated with primary surgery in comparison to CRT. Although this result may reflect a decreased interest in dilation among patients chronically PEG dependent, it does highlight a potentially increased late effect of primary surgical therapy. However, since osteonecrosis and esophageal stricture can both develop many years after radiotherapy [14], additional follow-up time may be needed to properly address this question. In a unique and potentially clinically meaningful finding, we have also shown that the impact of chemotherapy depends on whether the patient is treated with primary versus adjuvant radiotherapy. In the former case, concurrent chemotherapy was associated with a significant survival advantage, consistent with multiple randomized studies [11]. 25
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modalities. Chronic pain, xerostomia, trismus, and neck fibrosis are late complications of head and neck locoregional therapy that are simply not evaluable in SEER-Medicare. Ultimately, prospective randomized trials are necessary to formally compare primary surgery with radiotherapy in OPC; two such trials are accruing patients in early T-category disease [3], and hopefully these studies will help draw final conclusions on the efficacy and toxicity of these dueling therapies. In the meantime, this paper represents one of the largest comparisons between surgery and RT in elderly patients treated for OPSCC, and our results support the use of either primary modality in the curative treatment of this disease. Patients should be counseled on the balance between immediate and late surgical morbidities with the acute and chronic toxicities of primary radiotherapy, with chronic gastrostomy use as the most obvious differentiator.
[4]
[5]
[6]
[7]
[8]
Presentation
[9]
Presented as poster presentation in ASCO Annual Meeting, 2017.
[10]
Research funding [11]
This study was supported by a research grant from Radiation Oncology Institute (ROI), ROI2015-915.
[12]
Role of funding source [13]
The funding source, Radiation Oncology Institute, had no analytical or editorial input to this manuscript.
[14]
Conflict of interest [15]
No author has any conflict of interest. [16]
References [1] Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol: Off J Am Soc Clin Oncol 2011;29(32):4294–301. [2] Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. J Clin Oncol: Off J Am Soc Clin Oncol 2015;33(29):3235–42. [3] Howard J, Masterson L, Dwivedi RC, et al. Minimally invasive surgery versus
[17]
26
radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma. Cochrane Database Syst Rev 2016;12:CD010963. Morisod B, Simon C. Meta-analysis on survival of patients treated with transoral surgery versus radiotherapy for early-stage squamous cell carcinoma of the oropharynx. Head Neck 2016;38(Suppl 1):E2143–50. de Almeida JR, Byrd JK, Wu R, et al. A systematic review of transoral robotic surgery and radiotherapy for early oropharynx cancer: a systematic review. The Laryngoscope 2014;124(9):2096–102. Yeh DH, Tam S, Fung K, et al. Transoral robotic surgery vs. radiotherapy for management of oropharyngeal squamous cell carcinoma – a systematic review of the literature. Eur J Surg Oncol: J Eur Soc Surg Oncol Brit Assoc Surg Oncol 2015;41(12):1603–14. Ling DC, Chapman BV, Kim J, et al. Oncologic outcomes and patient-reported quality of life in patients with oropharyngeal squamous cell carcinoma treated with definitive transoral robotic surgery versus definitive chemoradiation. Oral Oncol Oct 2016;61:41–6. Maggiore R, Zumsteg ZS, BrintzenhofeSzoc K, et al. The older adult with locoregionally advanced head and neck squamous cell carcinoma: knowledge gaps and future direction in assessment and treatment. Int J Radiat Oncol Biol Phys 2017;98(4):868–83. Potosky AL, Riley GF, Lubitz JD, Mentnech RM, Kessler LG. Potential for cancer related health services research using a linked Medicare-tumor registry database. Med Care Aug 1993;31(8):732–48. Beadle BM, Liao KP, Chambers MS, et al. Evaluating the impact of patient, tumor, and treatment characteristics on the development of jaw complications in patients treated for oral cancers: a SEER-Medicare analysis. Head Neck 2013;35(11):1599–605. Sher DJ, Adelstein DJ, Bajaj GK, et al. Radiation therapy for oropharyngeal squamous cell carcinoma: executive summary of an ASTRO Evidence-Based Clinical Practice Guideline. Pract Radiat Oncol 2017. Adelstein D, Gillison ML, Pfister DG, et al. NCCN Guidelines Insights: head and neck cancers, version 2.2017. J Natl Comprehen Cancer Network: JNCCN. 2017;15(6):761–70. Hoxbroe Michaelsen S, Gronhoj C, Hoxbroe Michaelsen J, Friborg J, von Buchwald C. Quality of life in survivors of oropharyngeal cancer: a systematic review and meta-analysis of 1366 patients. Eur J Cancer 2017;78:91–102. Ahlberg A, al-Abany M, Alevronta E, et al. Esophageal stricture after radiotherapy in patients with head and neck cancer: experience of a single institution over 2 treatment periods. Head Neck 2010;32(4):452–61. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84(5):1198–205. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11(1):21–8. Dinan MA, Curtis LH, Carpenter WR, et al. Stage migration, selection bias, and survival associated with the adoption of positron emission tomography among medicare beneficiaries with non-small-cell lung cancer, 1998–2003. J Clin Oncol: Off J Am Soc Clin Oncol 2012;30(22):2725–30.
Contents lists available at ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Comparative effectiveness of primary radiotherapy versus surgery in elderly patients with locally advanced oropharyngeal squamous cell carcinoma
T
⁎
David J. Shera, , Jingsheng Yanb, Andrew Dayc, Baran D. Sumerc, Nhat-Long Phamd, Saad Khane, Hong Zhub a
Department of Radiation Oncology and Division of Outcomes and Health Services Research, UT Southwestern Medical Center, Dallas, TX, USA Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, USA c Department of Otolaryngology-Head & Neck Surgery, UT Southwestern Medical Center, Dallas, TX, USA d Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA e Department of Medical Oncology, UT Southwestern Medical Center, Dallas, TX, USA b
A R T I C LE I N FO
A B S T R A C T
Keywords: Oropharynx cancer Chemoradiotherapy Combined-modality therapy SEER-Medicare
Objectives: To determine the comparative effectiveness of primary radiotherapy (RT) and primary surgery (PS) for locally advanced oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: Eligible individuals were patients in the SEER-Medicare registry diagnosed with locally advanced OPSCC between 2000 and 2011. Patients were categorized as receiving either primary RT ± chemotherapy, or PS ± adjuvant RT or chemoradiotherapy (CRT). Overall survival (OS) was analyzed using Cox multivariable analysis (MVA). Risks of gastrostomy dependence (GD), esophageal stricture (ES), and osteoradionecrosis (ORN) were analyzed using logistic regression. Results: A total of 2754 patients (69% RT, 31% PS) were included in this cohort, with a median age of 72 years. Patients treated with RT, CRT and PS experienced 3-year OS outcomes of 36.1%, 52.8%, and 54.9%, respectively (p < 0.001). Increasing age, unmarried status, increasing comorbidity, lower income, base of tongue (BOT) site, higher stage, no prior PET, and RT alone (but not CRT) were associated with inferior OS. Independent predictors of GD at 6 months included black race, BOT site, advanced stage, and CRT. The risks of ORN and stricture were not associated with treatment modality. Concurrent chemotherapy improved OS with definitive RT but had no impact in adjuvant RT. Only cisplatin- and taxane-containing regimens improved OS, but all concurrent agents, including cetuximab, significantly worsened GD. Conclusion: Local therapy decisions for locally advanced OPSCC must be individualized, with CRT increasing acute and chronic GD. The differential survival impact of concurrent chemotherapy in the definitive and adjuvant setting may be a consideration in decision-making.
Introduction The prevalence of oropharyngeal squamous cell carcinoma (OPSCC) has increased dramatically, and it is now the most commonly diagnosed head and neck malignancy in the United States [1]. This increase, driven by human papillomavirus (HPV) infection, has been seen in elderly populations as well [2]. As radiotherapy and surgical techniques have improved, primary surgical therapy and radiation therapy are both viable treatment approaches for this disease. The opportunity to spare patients the toxicity of concurrent chemoradiotherapy (CRT) or even any adjuvant radiotherapy (RT) is the main benefit of surgery, whereas eliminating any immediate surgical risk or delayed surgical complication are strengths of definitive RT or CRT. ⁎
Outcome comparisons between upfront surgery and radiotherapy are generally small and all retrospective, as two prospective trials will not be completed for several years [3]. The general consensus from these studies is that survival outcomes are not significantly different [4,5], but the potential to minimize the exposure of patients to CRT and its complications may favor an initial surgical approach [6,7]. Yet there is a gap in comparing these two locoregional modalities in the elderly, which comprises a significant percentage of the afflicted population [8]. Given the well-known toxicities in delivering concurrent chemotherapy to older patients, the therapeutic ratios of these two treatments take on added importance. In this study, we have used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to compare survival and toxicity
Corresponding author at: Department of Radiation Oncology, UT Southwestern Medical Center, 5810 Forest Park Drive, Dallas, TX 75390, USA. E-mail address: [email protected] (D.J. Sher).
https://doi.org/10.1016/j.oraloncology.2018.11.004 Received 28 August 2018; Received in revised form 26 October 2018; Accepted 3 November 2018 1368-8375/ © 2018 Published by Elsevier Ltd.
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outcomes in elderly patients with locally advanced OPC treated with upfront surgery versus definitive RT or CRT. We compared overall survival outcomes, as well as gastrostomy use and dependence, esophageal stricture, and osteonecrosis, in order to understand the therapeutic ratios of these two competing treatments. Moreover, we analyzed the differential importance of concurrent chemotherapy in the definitive and postoperative settings, including a focus on the impact of alternative chemotherapy regimens. Methods Data sources This cohort was created from the Surveillance, Epidemiology and End Results (SEER)-Medicare database, which links health care claims for fee-for-service Medicare enrollees with patient demographic and tumor-specific data recorded by SEER cancer registries. The Medicare program provides health care benefits to 97% of the U.S. population aged 65 years or older, and approximately 94% of SEER patients 65 years or older have been successfully linked with their Medicare claims [9]. Cohort definition Fig. 1 details the inclusion and exclusion characteristics that defined the cohort composition. Patients were aged 66 years or older and diagnosed with “regional” or “distant” squamous cell carcinoma of the oropharynx (Table 1) between the years 2000 and 2011, and Part A/B coverage was mandatory for 1 year prior diagnosis to 1 year following diagnosis. Because some locally advanced primary tumors were coded as “distant” historical stage in the SEER registry (e.g. extension to larynx/hypopharynx, mandible, extrinsic tongue musculature, other bone or hard palate), patients with this stage were included in the analysis. The first treatment (either surgery, RT, or chemotherapy) was required to have started within 6 months of diagnosis. Patients needed to receive either definitive surgery or definitive RT for inclusion. Treatment assignments Claims for at least 20 RT fractions were required for patients to have been coded as receiving curative-intent radiotherapy, within 12 weeks of starting treatment; shorter regimens may have been palliative in intent. Concurrent chemoradiotherapy was defined by a chemotherapy claim between 3 weeks prior to starting RT and the end of RT. Chemotherapy delivered prior to 3 weeks before RT was considered induction therapy, and these patients were excluded, since subsequent radiotherapy selects for favorable responders. Adjuvant RT was assigned after surgery if the first RT claim was present within 90 days of surgery, and adjuvant CRT was assigned if chemotherapy was administered between 3 weeks before RT to the last RT claim. Patients who underwent a diagnostic tonsillectomy without neck dissection were classified as receiving primary RT. Diagnostic lymph node excisions were not considered as a primary surgery; only neck dissections were considered a curative-intent operation. Chemotherapy agents were categorized as cisplatin, carboplatinonly, taxane-containing (including doublets with a platinum), cetuximab-only, and other.
Fig. 1. Cohort definition.
that time may have had dysphagia from disease progression. The date of last use was the last claim for nutrition. The presence of a clinically relevant early esophageal stricture was defined as a dilation code within the first year of surviving patients. The presence of a clinically relevant bone complication was coded using the methodology of Beadle et al. [10] One year was chosen as the primary analysis for these latter two toxicities since subsequent procedures may be more likely due to disease progression. For gastrostomy dependence analyses at 6 and 12 months, the denominators were patients alive at 6 and 12 months, respectively.
Outcomes
Chemotherapy analyses
Overall survival was calculated from the date of diagnosis to the date of death. All patients were analyzed for toxicity endpoints, with stage serving as a covariate. Gastrostomy use was evaluated at 3 time points: any, 6 months or longer, and 12 months or longer. Gastrostomy use required a claim for enteral nutrition from diagnosis to 3 months from the last treatment; patients who first used enteral feedings after
We performed several sensitivity analyses on the relative benefits and harms of chemotherapy in these two cohorts. First, an interaction term was placed in the multivariable model for overall survival to assess whether the primary therapy modality (i.e. RT or surgery) was an effect modifier of the impact of chemotherapy. Subset analyses were then performed in primary radiotherapy patients and in surgical patients 19
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Table 1 (continued)
Table 1 Patient characteristics. Abbreviations: SE = standard error; CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. PET = positron emission tomography. Characteristic
Patient characteristics Age (median, IQR) Age (quartile) ≤68 69–72 73–77 ≥78 Gender Female Male Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure Yes No SEER region Northeast South Midwest West Median census tract income ≤25% 25–50% 50–75% ≥75% Area of residence Metropolitan Nonmetropolitan % HS diploma ≤70% 70–85% 85–90% ≥90% Disease characteristics Primary site Tonsil Base of tongue Other Historic stage Regional Distant Grade I II III Other
Entire cohort (n = 2754)
Primary radiotherapy (n = 1913)
Primary surgery (n = 841)
P value
72, 69–77
73, 69–78
71, 68–76
< 0.001 < 0.001
665 750 678 661
434 511 470 498
231 239 208 163
(24%) (27%) (25%) (24%)
(23%) (27%) (25%) (26%)
Characteristic
Chemotherapy Cisplatin Carboplatinonly Taxanecontaining Cetuximabonly Other RT modality 2D/3D IMRT PET use Yes No
(27%) (28%) (25%) (19%) 0.522
776 (28%) 1978 (72%)
546 (29%) 1367 (71%)
230 (27%) 611 (73%)
2429 (88%) 214 (8%) 111 (4%)
1682 (88%) 160 (8%) 71 (4%)
747 (89%) 54 (6%) 40 (5%)
1490 (54%) 1264 (46%)
1019 (53%) 894 (47%)
471 (56%) 370 (44%)
0.107
Entire cohort (n = 2754)
Primary radiotherapy (n = 1913)
Primary surgery (n = 841)
596 (39%) 108 (7%)
515 (39%) 95 (7%)
81 (41%) 13 (12%)
322 (21%)
286 (21%)
36 (11%)
365 (24%)
331 (25%)
34 (17%)
141 (9%)
108 (8%)
33 (17%)
1689 (71%) 675 (29%)
1351 (71%) 562 (29%)
338 (75%) 113 (25%)
1583 (57%) 1171 (43%)
1207 (63%) 706 (37%)
376 (45%) 465 (55%)
P value
< 0.001
0.068
< 0.001
who received adjuvant radiotherapy. 0.184
Statistical methods
0.113 1392 (51%) 655 (24%) 244 (9%) 198 (7%)
965 474 185 146
(50%) (25%) (10%) (8%)
1669 (61%) 1085 (39%)
1162 (61%) 751 (39%)
507 (60%) 334 (40%)
499 (18%) 779 (28%) 279 (10%) 1197 (43%)
321 585 181 826
178 (21%) 194 (23%) 98 (12%) 371 (44%)
Summary statistics for patient characteristics were reported using medians and interquartile ranges (IQR) for continuous variables, and using counts and percentages for categorical variables. Patient characteristics, disease characteristics, and treatment characteristics were compared between primary radiotherapy and primary surgery using the χ 2 -test. The overall survival was estimated using the Kaplan-Meier method. Median survival time and 95% confidence intervals (CI) were reported. Univariable and multivariable Cox regression analyses were used to assess the association between the overall survival and patient, disease, treatment characteristics. Variables with a univariable p-value of 0.2 or less were entered in a backward selection algorithm to yield the parsimonious multivariable regression model. The assumption for proportional hazards was evaluated by using scaled Schoenfeld residuals. Hazard ratios and 95% confidence intervals (CI) were reported. Univariable logistic regression and multivariable logistic regression with the backward selection algorithm were used to identify the predictors for toxicity endpoints at 1 and 3 years. Odds ratios and 95% confidence intervals (CI) were reported. Two-sided p-values were reported and a p-value less than 0.05 was considered statistically significant. All analyses were conducted using SAS version 9.4 (Cary, NC).
427 (51%) 181 (22%) 59 (7%) 52 (6%) 0.821
< 0.001 (17%) (31%) (9%) (43%)
0.826 217 (8%) 1404 (51%) 750 (27%) 360 (14%)
156 978 518 246
(8%) (51%) (27%) (13%)
61(7%) 426 (51%) 232 (28%) 114 (14%)
2292 (83%) 462 (17%)
1578 (82%) 335 (18%)
714 (85%) 127 (15%)
562 902 475 792
405 643 305 545
157 259 170 247
0.119
0.023 (20%) (33%) (17%) (29%)
(21%) (34%) (16%) (28%)
(19%) (31%) (20%) (29%)
Results Patient and treatment characteristics
0.391 933 (34%) 1297 (47%) 524 (19%)
633 (33%) 915 (48%) 365 (19%)
300 (36%) 382 (45%) 159 (19%)
2285 (83%) 469 (17%)
1585 (83%) 328 (17%)
700 (83%) 141 (17%)
140 (5%) 955 (35%) 1047 (38%) 612 (22%)
96 (5%) 642 (34%) 681 (36%) 494 (26%)
44 (5%) 313 (37%) 366 (44%) 118 (14%)
578 (30%) 1335 (70%)
0 0
0 0 0
390 (46%) 254 (30%) 197 (23%)
Patient characteristics (n = 2754) are shown in Table 1. The median age of the cohort was 72 years, and the majority (72%) of patients were male. Nearly 88% of the individuals were white. There was a smokingrelated claim in 61% of all patients. The historic stage was regional and distant in 83%, and 17%, respectively. Primary radiotherapy was used in 69% of all patients; out of these individuals, radiation alone and concurrent chemotherapy were implemented in 30% and 70% of the group, respectively. Patients treated with radiotherapy alone were slightly but significantly more likely to have higher Charlson-Deyo comorbidities scores (50% vs 56%, 27% vs. 27%, 14% vs 9%, and 9% vs. 8% with scores of 0, 1, 2, and 3–7, for RT vs. CRT, respectively, p = 0.022). These individuals were also older (median 76, IQR 70–81 years) than those treated with CRT (median 71, IQR 68–76 years, p < 0.001). Patients older than 72 years (median) were less likely to receive any concurrent systemic therapy (44% vs. 53%, p < 0.001), and of those patients receiving systemic treatment, older patients were more likely to receive cetuximab (34% vs. 18%, OR
0.807
< 0.001
Treatment characteristics Primary RT RT alone 578 (30%) Concurrent 1335 (70%) CRT Primary surgery Surgery only 390 (47%) Adjuvant RT 254 (30%) Adjuvant CRT 197 (23%)
20
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Table 2 Overall survival results. A hazard ratio over 1 means increased mortality. Abbreviations: SE = standard error; CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery + C/RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
3-year survival % (SE)
Univariable Analysis (95% CI)
Multivariable analysis
62.9 56.5 48.2 31.3
(2.0) (2.0) (2.1) (1.9)
Reference 1.24 (1.07–1.44) 1.56 (1.35–1.80) 2.49 (2.16–2.87)
Reference 1.24 (1.06–1.46) 1.50 (1.28–1.75) 2.03 (1.74–2.38)
51.1 (1.2) 46.2 (1.9)
Reference 1.21 (1.09–1.34)
51.3 (1.1) 36.0 (3.5) 42.6 (5.2)
Reference 1.43 (1.21–1.69) 1.15 (0.89–1.48)
55.3 (1.4) 43.4 (1.5)
Reference 1.47 (1.33–1.61)
Reference 1.32 (1.18–1.46)
56.8 44.7 35.0 25.6
(1.4) (2.1) (3.4) (3.5)
Reference 1.54 (1.37–1.73) 1.81 (1.53–2.14) 2.34 (1.96–2.79)
Reference 1.51 (1.34–1.71) 1.63 (1.37–1.93) 1.93 (1.61–2.31)
50.0 (1.6) 50.5 (1.3)
Reference 0.99 (0.90–1.10)
51.0 50.6 48.5 45.8
(1.6) (2.4) (1.9) (3.2)
Reference 1.07 (0.93–1.22) 1.08 (0.96–1.21) 1.15 (0.98–1.36)
58.8 51.5 48.5 35.8
(2.8) (2.0) (1.4) (3.4)
Reference 1.24 (1.04–1.47) 1.27 (1.08–1.48) 1.75 (1.42–2.16)
49.6 (1.1) 50.2 (2.5)
Reference 0.97 (0.85–1.11)
53.8 51.8 47.6 45.1
(1.9) (2.5) (1.8) (2.2)
Reference 1.07 (0.92–1.24) 1.12 (0.99–1.27) 1.26 (1.10–1.45)
55.6 (1.8) 50.3 (1.5) 38.0 (2.3)
Reference 1.16 (1.04–1.29) 1.60 (1.40–1.82)
44.4 (4.4) 46.7 (1.7) 51.1 (1.7)
Reference 0.95 (0.77–1.18) 0.81 (0.66–1.01)
53.1 (1.1) 33.4 (2.4)
Reference 1.70 (1.50–1.92)
Reference 1.77 (1.55–2.02)
54.9 (1.8) 36.1 (2.1) 52.8 (1.5)
Reference 1.59 (1.40–1.80) 1.03 (0.92–1.15)
Reference 1.24 (1.08–1.42) 1.06 (0.94–1.20)
48.7 (1.3) 55.9 (2.2)
Reference 0.82 (0.72–0.93)
59.5 (1.4) 37.8 (1.5)
Reference 1.68 (1.52–1.85)
P value
< 0.001
< 0.001
< 0.001
0.018 Reference 1.02 (0.86–1.22) 1.10 (0.94–1.30) 1.37 (1.09–1.72)
< 0.001 Reference 1.19 (1.06–1.34) 1.43 (1.24–1.65)
< 0.001
0.008
< 0.001 Reference 1.62 (1.46–1.81)
site surgery only, and 173 (21%) underwent neck dissection only.
2.41 (95% CI 1.87–3.11, p < 0.001). Of the patients treated with initial surgery, 47%, 30%, and 23% received no adjuvant therapy, adjuvant radiotherapy, and adjuvant chemoradiotherapy, respectively. Of the 841 patients who underwent surgery, 371 (44%) underwent primary site surgery plus neck dissection, 297 (35%) received primary
Overall survival The median follow-up duration for surviving patients was 3.3 years. 21
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Fig. 2. Overall survival.
term gastrostomy dependence were similar to any dependence, including treatment (p < 0.001), except radiation alone was almost significantly improved in comparison to primary surgery (OR 0.76, 95% CI 0.55–1.03). Finally, 20% (n = 406) of surviving patients were gastrostomy-dependent at least one year from the end of treatment. Multivariable regression disclosed several variables predictive of long-term gastrostomy dependence, including older age, non-married status, base of tongue primary site, and advanced stage. Treatment with CRT (OR 1.66, 95% CI 1.28–2.15) but not RT alone (OR 0.84, 95% CI 0.58–1.22) was strongly associated with gastrostomy-dependence at one year in comparison to surgery.
Table 2 shows the univariable and adjusted predictors of overall survival. Younger age, married status, lower comorbidity score, higher census tract income, tonsil site, regional (versus distant) stage, PET use, and treatment type (p < 0.001) were all associated with improved survival. Using primary surgery as the reference, radiation alone was significantly related to inferior survival (HR 1.24, 95% CI 1.08–1.42), whereas there was no difference between CRT and surgery (HR 1.06, 95% CI 0.94–1.20). Survival curves are shown in Fig. 2. Sensitivity analyses on survival In the first sensitivity analysis, we excluded patients from the surgical cohort who underwent a non-transoral surgery (n = 172). The results were essentially identical. We also performed a subset analysis of locally advanced patients treated with RT, CRT or primary site surgery plus neck dissection. In this regression, treatment type was again associated with overall survival (p = 0.035), but the distinction was between surgery and RT (HR 1.20, 95% CI 1.01–1.42) and not surgery and CRT (HR 1.02, 95% CI 0.87–1.20).
Esophageal dilation The crude risk of esophageal dilation within one year of the end of treatment was 4.3% (n = 88) for surviving patients. On multivariable analysis, only region (Northeast, South, and Midwest all significantly greater than West) were associated with increased risk of stricture. Treatment type was not associated with this toxicity. Among 3 year survivors, chemoradiotherapy was actually protective on multivariable analysis, with the OR 0.62 (95% CI 0.43–0.91) in comparison to primary surgery (p = 0.0042 for the 3-way comparison).
Gastrostomy dependence Enteral feeding was evaluated in 3 ways: any enteral feeding, gastrostomy use past 6 months from the end of last treatment, and gastrostomy use past 12 months from the end of last treatment. Table 3 shows the multivariable predictors of any gastrostomy use. Among all patients, 43% (n = 1182) of individuals used enteral feeding at some point in the first year of treatment. Treatment type was associated with any gastrostomy use (p < 0.0001), with chemoradiotherapy significantly increasing the risk of enteral feedings (OR 2.44, 95% CI 2.04–2.93) over primary surgery; patients treated with radiotherapy alone were not significantly more likely to require a gastrostomy (OR 0.96, 95% CI 0.76–1.21). A total of 21% (n = 632) of all patients were gastrostomy-dependent past 6 months (Table 4). The multivariable predictors of medium-
Bone toxicity Ninety-seven surviving patients (4.7%) experienced a bone toxicity within the first year of finishing radiotherapy. No patients treated with surgery alone developed a bone toxicity. In restricting the analysis to patients who received radiation therapy, there were no significant predictors of osteonecrosis on multivariable analysis. There was also no relationship between treatment and osteonecrosis when restricting the analysis to 3 years survivors.
22
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Table 3 Use of gastrostomy tube at any point. Abbreviations CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery and RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
Gastrostomy use %
Univariable analysis (95% CI)
41.5 44.8 44.5 40.5
Reference 1.14 (0.93–1.413) 1.13 (0.91–1.405) 0.96 (0.77–1.196)
43.6 41.2
Reference 0.91 (0.77–1.075)
43.3 43.5 33.3
Reference 1.01 (0.76–1.334) 0.65 (0.44–0.979)
45.4 40.0
Reference 0.80 (0.69–0.936)
45.2 46.3 43.3 36.9
Reference 1.04 (0.87–1.258) 0.93 (0.71–1.226) 0.71 (0.52–0.963)
38.3 45.9
Reference 1.36 (1.17–1.594)
42.0 40.7 44.7 45.9
Reference 0.95 (0.77–1.170) 1.11 (0.93–1.336) 1.17 (0.90–1.520)
41.1 42.1 43.5 46.1
Reference 1.04 (0.81–1.346) 1.10 (0.87–1.396) 1.22 (0.87–1.719)
42.5 45.0
Reference 1.11 (0.91–1.355)
42.4 41.9 44.2 42.9
Reference 0.98 (0.78–1.232 1.08 (0.89–1.305) 1.02 (0.82–1.268)
37.8 48.7 37.6
Reference 1.56 (1.32–1.853) 0.99 (0.79–1.234)
42.9 45.2 41.7
Reference 1.10 (0.77–1.576) 0.96 (0.67–1.364)
42.7 44.1
Reference 1.06 (0.87–1.297)
32.6 30.8 54.7
Reference 0.92 (0.73–1.157) 2.50 (2.09–2.989)
45.5 48.2
Reference 1.11 (0.93–1.329)
48.4 35.5
Reference 0.59 (0.50–0.686)
Multivariable analysis
P value
< 0.001 Reference 1.34 (1.14–1.57)
< 0.001 Reference 1.51 (1.26–1.80) 1.00 (0.80–1.26)
< 0.001 Reference 0.96 (0.76–1.21) 2.44 (2.04–2.93)
was significant (HR 0.70, p = 0.03). This result means that the impact of concurrent chemotherapy is significantly different in the definitive and adjuvant setting: it is beneficial in primary RT patients but detrimental in primary surgery patients (adjusted HR 1.28, 95% CI 0.95–1.71). Indeed, when just analyzing patients who received surgery
Chemotherapy In a subset analysis restricted to patients receiving radiotherapy, with concurrent chemotherapy as an independent variable and an interaction term for primary therapy*chemotherapy, the interaction term 23
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Table 4 Use of gastrostomy tube at 6 months. Abbreviations CI = confidence interval; HS = high school; RT = radiotherapy; CRT = chemoradiotherapy; IMRT = intensity modulated radiation therapy. Characteristic Patient characteristics Age (quartile) ≤68 69–72 73–77 ≥78 Gender Male Female Race White Black Other Marital status Married Other Charlson-Deyo comorbidity 0 1 2 3–7 Tobacco exposure No Yes SEER region West Northeast South Midwest Median census tract income ≥75% 50–75% 25–50% ≤25% Area of residence Metropolitan Non-metropolitan % HS diploma ≥90% 85–90% 70–85% ≤70% Disease characteristics Primary site Tonsil Base of tongue Other Grade I II III Historic stage Regional Distant Treatment characteristics Treatment Surgery and RT RT alone CRT RT modality 2D/3D IMRT PET use Yes No
Gastrostomy use %
Univariable analysis (95% CI)
Multivariable analysis
26.2 24.7 30.5 27.2
Reference 0.92 (0.71–1.20) 1.24 (0.95–1.61) 1.05 (0.80–1.39)
Reference 0.92 (0.70–1.20) 1.32 (1.01–1.73) 1.21 (0.91–1.62)
26.5 28.6
Reference 1.11 (0.91–1.37)
26.6 34.7 21.4
Reference 1.47 (1.05–2.04) 0.75 (0.44–1.28)
27.4 26.6
Reference 0.96 (0.80–1.16)
26.9 29.8 31.7 26.1
Reference 1.15 (0.92–1.45) 1.26 (0.90–1.76) 0.96 (0.64–1.43)
25.4 28.1
Reference 1.15 (0.94–1.39)
26.3 26.6 27.2 30.5
Reference 1.02 (0.78–1.32) 1.04 (0.83–1.31) 1.23 (0.90–1.69)
24.9 26.7 27.8 28.9
Reference 1.10 (0.80–1.51) 1.16 (0.87–1.56) 1.23 (0.80–1.88)
27.0 27.5
Reference 1.03 (0.80–1.32)
27.5 26.9 26.1 29.0
Reference 0.97 (0.73–1.29) 0.93 (0.73–1.18) 1.08 (0.82–1.41)
22.3 31.7 24.1
Reference 1.62 (1.31–2.01) 1.11 (0.83–1.47)
27.6 28.8 27.4
Reference 1.06 (0.67–1.67) 0.99 (0.63–1.56)
25.7 34.3
Reference 1.51 (1.18–1.93)
Reference 1.39 (1.08–1.80)
21.4 17.8 34.2
Reference 0.80 (0.59–1.08) 1.91 (1.53–2.39)
Reference 0.76 (0.55–1.03) 1.83 (1.46–2.30)
28.4 29.1
Reference 1.04 (0.83–1.29)
28.5 24.9
Reference 0.83 (0.69–1.01)
P value
0.027
0.046 Reference 1.48 (1.049–2.08) 0.77 (0.446–1.32)
< 0.001 Reference 1.52 (1.22–1.89) 1.11 (0.83–1.48)
0.010
< 0.001
When categorizing chemotherapy into specific agents among patients treated with primary radiotherapy, a significant survival benefit (Table 5) over radiotherapy alone was restricted to treatment with cisplatin (HR 0.78, 95% CI 0.65–0.93) or a taxane-containing regimen (HR 0.77, 95% CI 0.64–0.94) (Table 5). In fact, there was a trend for
and adjuvant RT or adjuvant CRT, there was no association between chemotherapy and survival (multivariable HR 1.1, 95% CI 0.84–1.52, p = 0.42). In contrast, among patients treated with primary radiotherapy, the use of chemotherapy was clearly associated with improved survival (HR 0.86, 95% CI 0.75–0.98, p = 0.03). 24
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Table 5 Impact of chemotherapy agent and outcome for patients receiving chemoradiotherapy. A hazard ratio over 1 means increased mortality. Abbreviations: AHR = adjusted hazard ratio; AOR = adjusted odds ratio. Chemotherapy
None Cisplatin Carboplatin-only Taxane-containing Cetuximab-only Other
3-Year Overall Survival
Any Gastrostomy
6-Month Gastrostomy
Stricture
%
AHR
%
AOR
%
AOR
%
AOR
36.1 59.8 44.7 59.2 39.9 48.3
Reference 0.78 (0.65–0.93) 0.79 (0.59–1.06) 0.77 (0.64–0.94) 1.16 (0.95–1.40) 0.82 (0.64–1.06)
30.8 56.5 52.6 57.3 51.7 50.0
Reference 2.74 (2.13–3.52) 2.35 (1.51–3.66) 2.86 (2.12–3.84) 2.27 (1.72–3.01) 2.16 (1.42–3.29)
17.8 34.3 32.1 37.9 30.3 37.0
Reference 2.58 (1.86–3.60) 2.07 (1.20–3.59) 2.89 (2.01–4.16) 1.95 (1.35–2.82) 2.96 (1.80–4.87)
11.9 7.4 13.7 6.6 7.6 11.1
Reference 0.61 (0.40–0.92) 1.26 (0.66–2.39) 0.50 (0.29–0.85) 0.63 (0.39–1.02) 0.89 (0.46–1.71)
In contrast, postoperative CRT did not add improve survival in comparison to adjuvant radiotherapy alone, suggesting surgery may be preferable in operable patients who may poorly tolerate concurrent chemotherapy. This result is hypothesis-generating, especially since information on margin status and other high-risk features was not available. On one hand, this difference may simply reflect the fact that the randomized data show a more questionable benefit to concurrent chemotherapy in the adjuvant setting [15]; on the other hand, one may argue that the risks of postoperative CRT are particularly pronounced in the elderly population, counterbalancing a smaller potential oncologic gain from the more intensive therapy. This analysis has also shown that while all concurrent drugs significant increased the risk of gastrostomy-dependence, only cisplatin and taxane-containing regimens led to a survival benefit. Carboplatin was not associated with improved survival, and most notably, cetuximab appeared to impair survival. This latter result confirms a similar finding on the adverse effect of the drug in elderly patients on the original Bonner trial [16], strongly arguing against its use in this population. Finally, it is also worth mentioning the potent improvement in overall survival (absolute difference over 20%) among patients staged with PET, a result that was maintained on multivariable regression. There are several possible explanations for this result, including the increased detection of occult metastatic disease, thus reducing the risk of local therapy in a patient with disseminated disease; stage migration from PET use has been seen in other disease sites [17]. The imaging information may have also facilitated superior local therapy through better radiotherapy targeting or even surgical planning. Finally, the use of PET may be a general marker of higher quality care, which could have improved survival through mechanisms not otherwise characterized. Claims-based studies suffer from several well-known limitations, and this analysis is no exception. While the analysis did control for smoking claims, the database does not include information on HPV or p16 status, and therefore an imbalance between treatment modalities may have confounded the results. The study only applies to elderly patients, and whether the same result would be seen in a younger cohort is unknown. This report is a retrospective analysis, and there is significant selection bias in which patients received initial surgical versus radiotherapeutic treatment. Because operative patients tend to be healthier with lower-volume disease, both survival and functional outcomes would be expected to be better. Similarly, the survival decrement seen in patients who received radiotherapy alone may partially relate to comorbid conditions that prevented the patient from receiving concurrent chemotherapy. In addition, the SEER-Medicare database does not provide information on recurrence patterns, so one cannot know whether locoregional control is superior with one treatment approach. Also, while we determined claims-based toxicities, ultimately patient-reported outcomes are the most important functional metric. Enteral feeding is only one measure of dysphagia, and does not include other aspects of swallowing that may be different in the two primary treatment
increasing mortality with use of cetuximab (HR 1.16, 95% CI 0.95–1.40). On the other hand, all concurrent regimens increased the risk of gastrostomy by over a factor of 2, which was significant at 6 months as well.
Discussion In this study, we have shown that in elderly individuals with locally advanced OPSCC, initial surgery is superior to RT alone but not CRT. Given that CRT is considered the standard-of-care in higher-stage disease [11], these findings confirm the absence of a significant survival difference between the standardly recommended surgical- and radiotherapy-based treatments for this condition [11,12]. Two literature reviews have suggested similar results [6,7], and the present study adds convincing, additional population-based data supporting this conclusion, despite a significant bias favoring primary operative therapy, including both selection bias for surgical candidacy and stage migration for more accurately staging surgical patients. In contrast, the late toxicity profiles differed by primary treatment modality. In particular, patients treated with definitive CRT experienced a significantly greater (and clinically meaningful) risk of any, 6month, and 12-month gastrostomy dependence in comparison to those treated with RT alone or initial surgery. Planning with IMRT has improved dramatically since the time of this study, and modern dysphagia-avoidance based planning may minimize the need for enteral support in patients treated today; of course, such improvements would be expected in the RT alone and postoperative settings as well. Nevertheless, dysphagia and chewing, in addition to xerostomia, dominate the chronic toxicity profile in patients treated for OPC [13]. Thus, while it is critical to recognize that operative patients are often selected for their lower volume, resectable disease as well as their potential for superior functional status and recovery, these data support the contention that avoiding concurrent CRT in this population will substantially improve their dysphagia. On the other hand, treatment modality was not associated with the need for an additional procedure to treat osteonecrosis, either at 1 or 3 years. This result does strongly suggest that differences in radiation dose with definitive versus adjuvant therapy either do not influence these complications, or the reduced dose is counteracted by the additional risk of surgical intervention. In addition, there was actually an increased risk of esophageal dilation among patients treated with primary surgery in comparison to CRT. Although this result may reflect a decreased interest in dilation among patients chronically PEG dependent, it does highlight a potentially increased late effect of primary surgical therapy. However, since osteonecrosis and esophageal stricture can both develop many years after radiotherapy [14], additional follow-up time may be needed to properly address this question. In a unique and potentially clinically meaningful finding, we have also shown that the impact of chemotherapy depends on whether the patient is treated with primary versus adjuvant radiotherapy. In the former case, concurrent chemotherapy was associated with a significant survival advantage, consistent with multiple randomized studies [11]. 25
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modalities. Chronic pain, xerostomia, trismus, and neck fibrosis are late complications of head and neck locoregional therapy that are simply not evaluable in SEER-Medicare. Ultimately, prospective randomized trials are necessary to formally compare primary surgery with radiotherapy in OPC; two such trials are accruing patients in early T-category disease [3], and hopefully these studies will help draw final conclusions on the efficacy and toxicity of these dueling therapies. In the meantime, this paper represents one of the largest comparisons between surgery and RT in elderly patients treated for OPSCC, and our results support the use of either primary modality in the curative treatment of this disease. Patients should be counseled on the balance between immediate and late surgical morbidities with the acute and chronic toxicities of primary radiotherapy, with chronic gastrostomy use as the most obvious differentiator.
[4]
[5]
[6]
[7]
[8]
Presentation
[9]
Presented as poster presentation in ASCO Annual Meeting, 2017.
[10]
Research funding [11]
This study was supported by a research grant from Radiation Oncology Institute (ROI), ROI2015-915.
[12]
Role of funding source [13]
The funding source, Radiation Oncology Institute, had no analytical or editorial input to this manuscript.
[14]
Conflict of interest [15]
No author has any conflict of interest. [16]
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